Synthesis of A-ring synthon of 19-NOR-1α,25-dihydroxyvitamin D3 from (D)-glucose

ABSTRACT

The present invention provides a method for the synthesis of an A-ring synthon phosphine oxide used in the preparation of 19-nor vitamin D compounds, and to novel synthetic intermediates formed during the synthesis. The new method prepares the phosphine oxide from (D)-glucose.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part application of U.S.patent application Ser. No. 10/205,453, filed Jul. 25, 2002, and nowU.S. Pat. No. 6,683,219, which application is based on and claimspriority from provisional patent Application No. 60/308,716 filed onJul. 30, 2001.

BACKGROUND OF THE INVENTION

The present invention relates to vitamin D compounds, and moreparticularly to the synthesis of an A-ring synthon used in thepreparation of 19-nor vitamin D compounds, and to novel syntheticintermediates formed during the synthesis.

The natural hormone, 1α,25-dihydroxyvitamin D₃ and its analog inergosterol series, i.e. 1α,25-dihydroxyvitamin D₂ are known to be highlypotent regulators of calcium homeostasis in animals and humans, andtheir activity in cellular differentiation has also been established,Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Manystructural analogs of these metabolites have been prepared and tested,including 1α-hydroxyvitamin D₃, 1α-hydroxyvitamin D₂, various side chainhomologated vitamins and fluorinated analogs. Some of these compoundsexhibit an interesting separation of activities in cell differentiationand calcium regulation. This difference in activity may be useful in thetreatment of a variety of diseases.

The discovery of the hormonally active form of vitamin D₃,1α,25-dihydroxyvitamin D₃ (1α,25-(OH)₂D₃ or calcitriol) has greatlystimulated research into its physiology and chemistry. As previouslynoted, it has been established that 1α,25-(OH)₂D₃ not only regulates themineral metabolism in animals and humans, but also exerts potent effectsupon cell proliferation and cellular differentiation. Therefore, thechemistry of vitamin D has been recently focused on the design andsynthesis of analogs that can exert selective biological actions.

Recently, a class of vitamin D analogs has been discovered, i.e. the socalled 19-nor-vitamin D compounds, which are characterized by thereplacement of the A-ring exocyclic methylene group (carbon 19), typicalof the vitamin D system, by two hydrogen atoms. Biological testing ofsuch 19-nor-analogs (e.g., 1α,25-dihydroxy-19-nor-vitamin D₃) revealed aselective activity profile with high potency in inducing cellulardifferentiation, and very low calcium mobilizing activity. Thus, thesecompounds are potentially useful as therapeutic agents for the treatmentof malignancies, or the treatment of various skin disorders. Differentmethods of synthesis of such 19-nor-vitamin D analogs have beendescribed. See for example Perlman et al., Tetrahedron Lett. 31, 1823(1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), DeLuca etal., U.S. Pat. No. 5,086,191, and DeLuca et al U.S. Pat. No. 5,936,133.

In one particularly advantageous method, the preparation of various19-nor-vitamin D compounds can be accomplished by the condensation of abicyclic Windaus-Grundmann type ketone having the desired side chainstructure with an A-ring phosphine oxide to the corresponding 19-norvitamin D analog followed by deprotection, particularly at C-1 and C-3in the latter compounds. One method of preparing the required A-ringphosphine oxides is to transform a methyl ester obtained from quinicacid into the desired A-ring synthon in accordance with the synthesisset forth in DeLuca et al U.S. Pat. No. 5,936,133. It is, however,desirable to provide an alternate method for preparing such A-ringphosphine oxides.

SUMMARY OF THE INVENTION

The present invention provides a new method for the synthesis of anA-ring synthon phosphine oxide used in the preparation of 19-nor vitaminD compounds, and to novel synthetic intermediates formed during thesynthesis. The new method prepares the phosphine oxide from (D)-glucose.

The A-ring synthon phosphine oxide to be prepared is represented by thefollowing structure

where the wavy line indicates a stereochemical center so that thephosphine oxide substituent may have either the R or S configuration,and may thus be obtained as a mixture of two isomers. Each of R³, R⁴ andR⁵ may independently be selected from a hydroxy protecting group, butpreferably R³ and R⁵ are both a t-butyldimethylsilyl hydroxy protectinggroup (abbreviated “TBS”) and R⁴ is a trimethylsilyl hydroxy protectinggroup (abbreviated “TMS”).

Preferably, the method of making the phosphine oxide comprises the stepsof:

-   -   converting D-glucose having the structure        to a 2-deoxy-glucose derivative having the structure        where R¹ is an alkyl group;    -   iodinating the 2-deoxy-glucose derivative to form a 5-iodinated        derivative having the structure    -   eliminating the iodine substituent of said 5-iodinated        derivative to form a 1-ether derivative having the structure    -   reducing the 1-ether derivative to form a 1-alcohol derivative        having the structure    -   converting the 1-alcohol derivative to a 1-protected derivative        having the structure        where R² is a hydroxy protecting group;    -   reducing the 1-protected derivative with a metal hydride to form        a 5-alcohol derivative having the structure    -   benzylating the 5-alcohol derivative to form a benzylated        derivative having the structure    -   hydrolyzing the benzyl derivative to form a 1-hydroxyl        derivative having the structure    -   oxidizing the 1-hydroxyl derivative to form a 1-ketone        derivative having the structure    -   converting the 1-ketone derivative to a 3,4,5-protected        derivative having the structure        where R³, R⁴ and R⁵ are each independently a hydroxy-protecting        group;    -   condensing the 3,4,5-protected derivative to an ester derivative        having the structure        where R⁶ is an alkyl group;    -   reducing the ester derivative with a metal hydride to form a        3,4,5-protected-1-alcohol derivative having the structure    -   and converting the 3,4,5-protected-1-alcohol to a phosphine        oxide having the structure

Alternate methods of converting D-glucose to the 2-deoxy-glucosederivative are illustrated in Schemes I and II.

The present invention is also directed toward novel intermediatecompounds formed during the method of making the phosphine oxide. Onesuch novel intermediate is the 5-alcohol derivative described in theabove process having the following chair configuration:

In the above drawing, Bn represents a benzyl group, and R² is a hydroxyprotecting group. This 5-alcohol derivative can also be illustrated bythe following Fischer projection drawing:

In one particularly preferred form, R² is a tert-butyldimethylsilyl(TBS) protecting group, and thus the above 5-alcohol derivative may beeither compound 15a or 15b in the synthesis illustrated hereinafter asScheme III. More specifically, compound 15a can be illustrated asfollows

and compound 15b can be illustrated as follows

where Bn is a benzyl group and R² is TBS. However, as noted above, R²can be any hydroxy-protecting group desired.

DETAILED DESCRIPTION OF THE INVENTION

As used in the description and in the claims, the term“hydroxy-protecting group” signifies any group commonly used for thetemporary protection of hydroxy functions, such as for example,alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafterreferred to simply as “silyl” groups), and alkoxyalkyl groups.Alkoxycarbonyl protecting groups are alkyl-O—CO— groupings such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,benzyloxycarbonyl or allyloxycarbonyl. The term “acyl” signifies analkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or acarboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl,succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, ora halo, nitro or alkyl substituted benzoyl group. The word “alkyl” asused in the description or the claims, denotes a straight-chain orbranched alkyl radical of 1 to 10 carbons, in all its isomeric forms.Alkoxyalkyl protecting groups are groupings such as methoxymethyl,ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl andtetrahydropyranyl. Preferred silyl-protecting groups are trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl,diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl andanalogous alkylated silyl radicals. The term “aryl” specifies a phenyl-,or an alkyl-, nitro- or halo-substituted phenyl group.

A “protected hydroxy” group is a hydroxy group derivatised or protectedby any of the above groups commonly used for the temporary or permanentprotection of hydroxy functions, e.g. the silyl, alkoxyalkyl, acyl oralkoxycarbonyl groups, as previously defined. The terms “hydroxyalkyl”,“deuteroalkyl” and “fluoroalkyl” refer to an alkyl radical substitutedby one or more hydroxy, deuterium or fluoro groups respectively.

Specific embodiments of the reactions of the new process are presentedin the following Examples. Process Schemes I, II, III and IV depict thestructures of the compounds described in these Examples, such thatproducts identified by Arabic numerals (e.g. 1, 2, 3, 3a, etc.)correspond to the structures so numbered in the Process Schemes.

EXAMPLES

Experimental

General: Unless otherwise noted, all air-sensitive reactions were rununder Ar atmosphere, and reagents were added through septa usingsyringes. Tetrahydrofuran and diethyl ether were distilled from Nabenzophenone ketyl prior to use. Pyridine, triethylamine,diisopropylamine, acetonitrile, methyl sulfoxide and methylene chloridewere distilled from calcium hydride. Toluene and MeOH were distilledfrom Na. N,N-Dimethylformamide was distilled from 4A molecular sieves.Ethyl acetate and 1,4-dioxane were reagent grade. All chemicals wereused as received. Column chromatography was performed on silica gel(Wako Pure Chem. Ind. Ltd. Wakogel C-200, ˜200 mesh). NMR spectra wererecorded in CDCl₃ on a Bruker ARX-400 MHz spectrometer. Chemical shiftsare reported in parts per million (ppm, δ) downfield fromtetramethylsilane. Mass spectra were recorded on a JEOL JMS-AX505HAspectrometer run at 70 eV for electronic ionization (EI).

Example 1

(See Scheme I)

Synthesis of 2-deoxy-glucose Derivative 7 from D-glucose

[Method A]

To a stirred suspension of D-glucose (1 g) in acetic anhydride (200 ml)was added 70% perchloric acid (1.2 mL). Additional D-glucose (49 g,total 50 g, 0.28 mol) was added in small portions over a period of 1.5h. The reaction mixture was maintained below 40° C. by occasionalcooling in an ice-water bath. After addition was complete, the solutionwas cooled to 20° C., and hydrogen bromide (33 wt. % solution in aceticacid, 200 mL) was added over a period of 30 min. After being stirred for3 h, the reaction mixture was diluted with methylene chloride(CH₂claim₂, 700 mL), and washed successively with ice-water and cold 5%sodium hydrogencarbonate (NaHCO₃), and then dried over magnesium sulfate(MgSO₄). The solvent was removed by reduced pressure to afford 2 (123 g)as a syrup. This product was used directly in the following reaction.

2: ¹H NMR (CDCl₃) δ: 2.04, 2.06, 2.10 and 2.11 (each 3H, s, COCH₃), 4.13(1H, d, J=10.7 Hz, 6-H), 4.28˜4.35 (2H, m, 5, 6-H), 4.85 (1H, dd, J=9.7,4.0 Hz, 2-H) 5.17 (1H, t, J=9.7 Hz, 3 or 4-H), 5.56 (1H, t, J=9.7 Hz, 3or 4-H), 6.62 (1H, d, J=4.0 Hz, 1-H).

The crude bromide 2 (56.1 g, 0.14 mol) was added slowly to a slurry ofzinc dust (60 g, 0.92 mol) in 50% aqueous acetic acid (500 mL) over aperiod of 1 h with mechanical stirring while maintaining the temperatureat −15˜−20° C. in dry ice-acetonitrile (CH₃CN) bath. After addition wascomplete, the reaction mixture was stirred for an additional 1 h at 0°C., and then the reaction mixture was filtered by suction. The filtratewas diluted with methylene chloride (800 mL) and extracted withice-water (3×250 mL). The organic layer was washed with cold saturatedNaHCO₃ (2×200 mL) and brine, and dried over MgSO₄. The solvent wasevaporated in vacuo to give 3 (37.5 g) as a syrup. This product was useddirectly in the next step.

3: ¹H NMR (CDCl₃) δ: 2.05, 2.13 and 2.15 (each 3H, s, COCH₃), 4.20 (1H,dd, J=12.0, 3.1 Hz, 6-H), 4.26 (1H, m, 5-H), 4.40 (1H, dd, J=12.0, 5.7Hz, 6-H), 4.85 (1H, dd, J=6.2, 3.2 Hz, 2-H), 5.23 (1H, dd, J=7.5, 5.7Hz, 4-H), 5.34 (1H, m, 3-H), 6.47 (1H, d, J=6.2 Hz, 1-H).

To a solution of the crude acetyl glucal 3 (12.5 g, 45.9 mmol) in dryMeOH (150 mL) was added a solution of sodium methoxide (NaOMe, 4.59mmol) in dry MeOH (1 mL) at room temperature. The reaction mixture wasstirred for 30 min and evaporated to dryness. The residue was dissolvedin dry N,N-dimethylformamide (DMF, 150 mL) at 0° C. and to this solutionwas added imidazole (9.4 g, 137.7 mmol) and tert-butyldimethylsilylchloride (10.4 g, 68.9 mmol). The reaction mixture was stirred for 3 hat room temperature, diluted with icewater, and extracted with 50% ethylacetate (AcOEt)-hexane. The organic extract was washed with brine, driedover MgSO₄, and evaporated in vacuo. The residue was purified bychromatography on silica gel (200 g) using 50% AcOEt-hexane to yield 4(7.15 g, 65% from D-glucose).

4: ¹H NMR (CDCl₃) δ: 0.11 (6H, s, Si—CH₃), 0.91 (9H, s, Si-tBu), 3.79(2H, m 6-H), 3.92 and 3.99 (each 1H, m, 4, 5-H), 4.26 (1H, m, 3-H), 4.72(1H, dd, J=6.1, 2.0 Hz, 2H), 6.31 (1H, dd, J=6.0, 2.0 Hz, 1-H).

Mass m/z (%): 260 (no M⁺), 224 (1), 203 (20), 185 (85), 167 (14), 75(100).

To a stirred, cold (0° C.) solution of 4 (4.42 g, 17.0 mmol) dissolvedin dry DMF (50 mL) and dry tetrahydrofuran (THF, 5 mL) was added sodiumhydride (60% dispersion in oil, 2.72 g, 68.0 mmol) and benzyl bromide(8.72 g, 51.0 mmol). Stirring was continued for 40 min at 0° C., and thereaction mixture was quenched with water. After extraction with 50%AcOEt-hexane, the combined organic extract was washed with brine, driedover MgSO₄, and evaporated to dryness. The residue was purified bychromatography on silica gel (150 g) using 3% AcOEt-hexane to afford 5(7.22 g, 97%).

5: ¹H NMR (CDCl₃) δ: 0.06 and 0.07 (each 3H, s, Si—CH₃), 3.87˜3.98 (4H,m, 4, 5, 6-H), 4.20 (1H, m, 3-H), 4.58 and 4.64 (each 1H, d, J=11.7 Hz,CH₂Ph), 4.74 and 4.86 (each 1H, d, J=11.2 Hz, CH₂Ph), 4.83 (1H, dd,J=6.1, 2.5 Hz, 2-H), 6.38 (1H, dd, J=6.2, 1.2 Hz, 1-H), 7.28-7.35 (10H,m, arom H).

Mass m/z (%): 440 (no M⁺), 383 (4), 332 (2), 277 (10), 253 (5), 221(100).

To a stirred solution of 5 (14.5 g. 32.9 mmol) in dry THF (50 mL) wasadded tetrabutylammonium fluoride (Bu₄NF, 1.0 M solution in THF, 65.8mmol) at 0° C. and stirring was continued for 2.5 h. The reactionmixture was quenched with ice-water and extracted with AcOEt. Theorganic extract was washed with brine, dried over MgSO₄, and evaporatedin vacuo. The residue was purified by chromatography on silica gel (200g) with 25% AcOEt-hexane to give 6 (9.42 g, 88%).

6: ¹H NMR (CDCl₃) δ: 3.80 (1H, dd, J=8.6, 6.2 Hz, 4-H), 3.85 (2H, d,J=4.1 Hz, 6-H), 3.93 (1H, dd, J=8.6, 4.1 Hz, 5-H), 4.23 (1H, ddd, J=6.2,2.7, 1.1 Hz, 3-H), 4.56 and 4.66 (each 1H, d, J=11.6 Hz, CH₂Ph), 4.72and 4.86 (each 1H, d, J=11.4 Hz, CH₂Ph), 4.88 (1H, dd, J=6.1, 2.7 Hz,2-H), 6.39 (1H, dd, J=6.1, 1.1 Hz, 1-H), 7.28˜7.35 (10H, m, arom H).

Mass m/z (%): 326 (M⁺, 0.2), 308 (0.1), 295 (0.1), 235 (3), 218 (12),189 (9), 163 (70), 91 (100).

To a stirred solution of 6 (9.41 g, 28.8 mmol) in dry MeOH (150 mL) wasadded portionwise mercury(II) acetate [(CH₃CO₂)₂Hg, 11.00 g, 34.5 mmol]over a 30 min period. After being stirred for 1.5 h at room temperature,the mixture was cooled to 0° C. To this solution was portionwise addedover a period of 1 h sodium borohydride (NaBH₄, 1.31 g, 34.5 mmol) andthe reaction mixture was stirred for 4 h. The mixture was filtered andthe filtrate was concentrated to a small volume. Water and chloroform(CHCl₃) were added, the organic phase was separated, and the aqueousphase was reextracted with CHCl₃. The organic extract was washed withwater, dried over MgSO₄, and evaporated to dryness. The residue wassubjected to chromatography on silica gel (150 g) using 30% AcOEt-hexaneto yield 7 (α-anomer: 6.92 g, 67%; β-anomer: 1.86 g, 18%) as a mixtureof anomeric isomers. 7a was isolated as a single isomer, while 7b wasobtained as a mixture of 7a and 7b.

7a (α-anomer): ¹H NMR (CDCl₃) δ: 1.65 and 2.29 (each 1H, m, 2-H), 3.30(3H, s, OCH₃), 3.50 (1H, t, J=9.4 Hz, 4-H), 3.64 (1H, dm, J=9.4 Hz,5-H), 3.75 (1H, dd, J=11.7, 4.1 Hz, 6-H), 3.81 (1H, dd, J=11.7, 3.0 Hz,6-H), 3.99 (1H, ddd, J=11.5, 9.4, 5.0 Hz, 3H), 4.63 and 4.67 (each 1H,d, J=11.6 Hz, CH₂Ph), 4.68 and 4.95 (each 1H, d, J=11.1 Hz, CH₂Ph), 4.80(1H, br. d, J=2.9 Hz, 1-H), 7.26˜7.36 (10H, m, arom H).

7b (β-anomer): ¹H NMR (CDCl₃) δ: 1.56 and 2.34 (each 1H, m, 2-H), 3.31(1H, m), 3.49 (3H, s, OCH₃), 4.40 (1H, dd, J=9.8, 2.0 Hz, 1-H).

7a and 7b: Mass m/z (%): 358 (M⁺, 0.7), 327 (1.5), 326 (1), 267 (87),235 (23), 91 (100).

Example 2

(See Scheme II):

Synthesis of 2-deoxy-glucose Derivative 7 from D-glucose

[Method B]

To a solution of the crude triacetyl glucal 3 (9.54 g, 35.0 mmol) inCH₃CN (150 mL) was successively added LiBr (3.65 g, 42.0 mmol), MeOH(2.25 g, 70.2 mmol), and p-toluenesulfonic acid monohydrate (p-TsOH.H₂O,954 mg) at room temperature. After being stirred for 3 h, the reactionmixture was concentrated to a small volume, diluted with cold 5% NaHCO₃solution, and extracted with CHCl₃. The organic extract was washed withice-water, dried over MgSO₄, and evaporated in vacuo. The residue waschromatographed on silica gel (150 g) using 30% AcOEt-hexane to give 8(9.01 g, 92% from D-glucose) (α-anomer:β-anomer=ca. 10:1). 8a wasisolated as a single isomer, while 8b was obtained as a mixture of 8aand 8b.

8a (α-anomer): ¹H NMR (CDCl₃) δ: 1.81 (1H, m, 2-H), 2.01, 2.04 and 2.10(each 3H, s, COCH₃), 2.25 (1H, m, 2-H), 3.35 (3H, s, OCH₃), 3.95 (1H,ddd, J=9.7, 4.7, 2.3 Hz, 5-H), 4.08 (1H, dd, J=12.3, 2.3 Hz, 6-H), 4.31(1H, dd, J=12.2, 4.7 Hz, 6-H), 4.84 (1H, d, J=3.1 Hz, 1-H), 5.00 (1H, t,J=9.7 Hz, 4-H), 5.30 (1H, ddd, J=11.5, 9, 7, 5.3 Hz, 3-H).

Mass m/z (%): 304 (M⁺, 0.1), 273 (2), 231 (4), 213 (25), 184 (9), 171(15), 111 (33), 100 (100).

8b (β-anomer): ¹H NMR (CDCl₃) δ: 1.73 (1H, m, 2-H), 2.03, 2.04 and 2.09(each 3H, s, COCH₃), 2.32 (1H, m, 2-H), 3.51 (3H, s, OCH₃), 3.62 (1H, m,5-H), 4.12 (1H, dd, J=12.2, 2.4 Hz, 6-H), 4.31 (1H, dd, J=12.2, 4.8 Hz,6-H), 4.48 (1H, dd, J=9.6, 2.0 Hz, 1-H), 5.00 (2H, m, 3, 4-H).

To a solution of 8a (α-anomer, 10.27 g, 33.8 mmol) in dry MeOH (150 mL)was added a solution of NaOMe (3.38 mmol) in dry MeOH (1 mL) at roomtemperature. The reaction mixture was stirred for 30 min and evaporatedto dryness. The residue was dissolved in dry CH₃CN (150 mL) and to thissolution was added benzaldehyde dimethyl acetal (7.70 g, 51.3 mmol) andp-TsOH.H₂O (1.03 g). The reaction mixture was stirred for 24 h at roomtemperature, concentrated to a small volume, and cold 5% NaHCO₃ andAcOEt were added. The organic phase was separated and the aqueous phasewas reextracted with AcOEt. The combined organic extract was washed withbrine, dried over MgSO₄, and evaporated in vacuo. The residue waspurified by chromatography on silica gel (200 g) using 30% AcOEt-hexaneto yield 9a (6.55 g, 73%).

9a (α-anomer): ¹HNMR (CDCl₃) δ: 1.80 (1H, m, 2-H), 2.24 (1H, m, 2-H),3.36 (3H, s, OCH₃), 3.49 (1H, t, J=9.0 Hz, 5-H), 3.76 (1H, t, J=9.5 Hz,6-H), 380 (1H, m), 4.20 (1H, m), 4.27 (1H, m), 4.82 (1H, d, J=3.4 Hz,1-H), 5.58 (1H, s, CHPh), 7.35-7.52 (5H, m, arom H).

Mass m/z (%): 266 (M⁺, 53), 234 (8), 179 (100), 105 (65).

To a solution of 9a (8.69 g, 32.7 mmol) in dry DMF-dry THF (150 mL-15mL) was added sodium hydride (60% dispersion in oil, 2.62 g, 65.4 mmol)at 0° C. and the mixture was stirred for 5 min. To this solution wasadded benzyl bromide (8.35 g, 49.1 mmol) and the mixture was stirred for1.5 h at 0° C. followed by stirring for 2 h at room temperature. Thereaction mixture was poured into ice-water and extracted with 50%AcOEt-hexane. The organic layer was washed with brine, dried over MgSO₄,and evaporated in vacuo. The residue was purified by chromatography onsilica gel (150 g) with 10% AcOEt-hexane to afford 10a (10.47 g, 90%).

L0a (α-anomer): ¹H NMR (CDCl₃) δ: 1.80 (1H, m, 2-H), 2.26 (1H, m, 2-H),3.33 (3H, s, OCH₃), 3.69 (1H, t, J=6.5 Hz), 3.79 (2H, m), 4.01 (1H, m),4.26 (1H, m), 4.68 and 4.83 (each 1H, d, J=11.9 Hz, CH₂Ph), 4.80 (1H, d,J=3.2 Hz, 1-H), 5.62 (1H, s, CHPh), 7.20˜7.50 (5H, m, arom H).

Mass m/z (%): 356 (M⁺, 43), 324 (6), 219 (10), 91 (100).

To a suspension of lithium aluminum hydride (LiAlH₄, 0.19 g, 5.05 mmol)in dry diethyl ether (10 mL) and dry CH₂Cl₂ (10 mL) was slowly added asolution of 10a (1.8 g, 5.05 mmol) in dry diethyl ether (10 mL) and dryCH₂claim₂ (10 mL) at room temperature. To this suspension wasportionwise added aluminum chloride (0.67 g, 5.05 mmol) and the mixturewas stirred for 1 h. Excess LiAlH₄ was destroyed by addition of wetether and filtered. The filtrate was diluted with ice-water andextracted with AcOEt. The organic extract was washed successively withcold 5% NaHCO₃ and brine, and dried over MgSO₄. Evaporation of thesolvent gave colorless syrup, which was purified by chromatography onsilica gel (75 g) using 30% AcOEt-hexane to give 7a (1.52 g, 84%).

Example 3

(See Scheme III):

In the following synthesis of the cyclohexanone derivative 19 from2-deoxy-glucopyranosides 7, we separated most of the syntheticintermediates 11˜18 which exist as two anomeric isomers or two isomersat C(1) position. In a practical synthesis, it is unnecessary toseparate those isomers in each reaction step.

A mixture of the two anomeric isomers 7a, 7b (6.40 g, 17.9 mmol),triphenylphosphine (Ph₃P, 5.64 g, 21.5 mmol), imidazole (3.51 g, 51.6mmol), iodine (12, 4.99 g, 19.6 mmol, freshly sublimated) in dry THF (70mL) was stirred for 5 h at 0° C. and overnight at room temperature.After being stirred for 6 h, additional Ph₃P, imidazole, and 12 (each0.5 equivalent) were added to the reaction mixture. The reaction mixturewas diluted with AcOEt, washed successively cold 5% NaHCO₃, 2N sodiumthiosulfate (Na₂S₂O₃), and brine. The organic extract was dried overMgSO₄ and evaporated in vacuo. The residue was purified bychromatography on silica gel (150 g) using 2% AcOEt-hexane to afford 11a(α-anomer: 5.52 g, 66%) and 11b (β-anomer: 1.34 g, 16%).

11a (α-anomer): ¹H NMR (CDCl₃) δ: 1.69 and 2.30 (each 1H, m, 2-H),3.31˜3.45 (3H, m, 4, 5, 6-H), 3.36 (3H, s, OCH₃), 3.54 (1H, dd, J=9.6,1.8 Hz, 6-H), 4.00 (1H, ddd, J=11.4, 8.5, 5.1 Hz, 3-H), 4.60 and 4.66(each 1H, d, J=11.5 Hz, CH₂Ph), 4.72 and 5.00 (each 1H, d, J=11.0 Hz,CH₂Ph), 4.83 (1H, br. D, J=2.8 Hz, 1-H), 7.27˜7.37 (10H, m, arom H).

Mass m/z (%): 468 (M⁺, 1), 437 (7), 377 (40), 345 (3), 271 (28), 253(6), 239 (8), 91 (100).

11a (β-anomer): ¹H NMR (CDCl₃) δ: 1.61 and 2.35 (each 1H, m, 2-H), 3.14(1H, ddd, J=8.7, 7.3, 2.5 Hz, 5-H), 3.29 (1H, dd, J=10.4, 7.4 Hz, 6-H),3.32 (1H, t, J=8.8 Hz, 4-H), 3.52 (3H, s, OCH₃), 3.54 (1H, dd, J=10.4,2.5 Hz, 6-H), 3.68 (1H, ddd, J=11.5, 8.5, 5.0 Hz, 3-H), 4.39 (1H, dd,J=9.7, 1.9 Hz, 1-H), 4.59 and 4.68 (each 1H, d, J=11.6 Hz, CH₂Ph), 4.70and 5.99 (each 1H, d, J=10.9 Hz, CH₂Ph), 7.28˜7.37 (10H, m, arom H).

Mass m/z (%): 469 (M⁺, 0.2), 436 (3), 377 (13), 345 (7), 271 (29), 253(4), 239 (9), 91 (100).

Powdered silver fluoride (AgF, 2.1 g, 16.5 mmol) was added to a solutionof 11a (2.0 g, 4.27 mmol) in dry pyridine (35 mL). After being stirredin the dark for 2 days, the reaction mixture was filtered and thefiltrate was partitioned between AcOEt and ice-water. After phaseseparation, the aqueous layer was reextracted with AcOEt. The combinedorganic extract was washed with water and brine, dried over MgSO₄, andevaporated to dryness. The residue was purified by chromatography onsilica gel (30 g) with 3% AcOEt-hexane to give 12a (1.35 g, 93%).

12a (α-anomer): ¹H NMR (CDCl₃) δ: 1.87 and 2.27 (each 1H, m, 2-H), 3.41(3H, s, OCH₃), 3.90 (2H, m, 3, 4-H), 4.63 and 4.71 (each 1H, d, J=11.7Hz, CH₂Ph), 4.73 and 4.78 (each 1H, d, J=11.7 Hz, CH₂Ph), 4.74 and 4.81(each 1H, br. S, 6-H), 4.86 (1H, t, J=3.2 Hz, 1-H), 7.28˜7.38 (10H, m,arom H).

To a stirred solution of 11b (895 mg, 1.91 mmol) in dry pyridine (15 mL)was added powdered AgF (486 mg, 3.82 mmol) and the reaction mixture wasstirred in the dark for 18 h at room temperature. Work-up similar tothat described above afforded 12b (618 mg, 95%).

12b (β-anomer): ¹HNMR(CDCl₃) δ: 1.86 (1H, m, 2-H), 2.28 (1H, ddd,J=14.0, 5.7, 3.4 Hz, 2-H), 3.50 (3H, s, OCH₃), 3.67 (1H, dt, J=7.0, 5.7Hz, 3-H), 3.96 (1H, d, J=5.7 Hz, 4-H), 4.58 and 4.73 (each 1H, d, J=11.6Hz, CH₂Ph), 4.63 (1H, s, 6-H), 4.64 (2H, s, CH₂Ph), 4.73 (1H, dd, J=5.9,3.4 Hz, 1-H), 4.78 (1H, s, 6-H), 7.27˜7.35 (10H, m, arom H).

To a stirred solution of 12a (1.07 g, 3.14 mmol) in 1,4-dioxane-water(15 mL, 2:1; v/v) was added palladium(II) chloride (PdCl₂, 113 mg, 0.64mmol) and the reaction mixture was heated at 60° C. for 1.5 h. AcOEt andwater were added to the mixture and the organic phase was separated. Theaqueous phase was reextracted with AcOEt and the combined organicextract was washed with water and brine, and then dried over MgSO₄.Removal of the solvent gave the residue, which was purified bychromatography on silica gel (30 g) using 50% AcOEt-hexane to yield 13(939 mg, 92%) in a mixture of 1α-OH (13a): 1β-OH (13b)=ca.6:1 ratio.

A mixture of 12b (1.34 g, 3.94 mmol) and PdCl₂ (140 mg, 0.79 mmol) in1,4-dioxanewater (21 mL, 2:1) was heated at 60° C. for 1.5 h. Work-upsimilar to that described above gave 13 (1.17 g, 91%) in a mixture of1α-OH (13a): 1β-OH (13b)=ca. 6:1 ratio.

13a (1-αOH): ¹H NMR (CDCl₃) δ: 2.03 and 2.32 (each 1H, m, 2-H), 2.64 (2Hm, 6-H), 3.98 (1H, d, J=7.5 Hz, 4-H), 4.04 (1H, ddd, J=8.0, 7.5, 4.1 Hz,3-H), 4.36 (1H, m, 1-H), 4.55, 4.61, 4.75 and 4.82 (each 1H, d, J=11.7Hz, CH₂Ph) 7.28˜7.39 (10H, m, arom H).

13b (1-βOH): ¹H NMR (CDCl₃) δ: 4.22 (1H, m, 1-H), 4.47, 4.54, 4.64 and4.79 (each 1H, d, J=11.7 Hz, CH₂Ph).

13a and 13b: Mass m/z (%): 326 (M⁺, 2), 308 (5), 278 (2), 235 (3), 217(2), 91 (100).

A mixture of 13a,b (1.95 g, 5.97 mmol), imidazole (813 mg, 11.9 mmol),tertbutyldimethylsilyl chloride (1.35 g, 8.96 mmol) in dry DMF (20 mL)was stirred at for 1 h 0° C. followed by for 1.5 h at room temperature.Additional imidazole (203 mg, 2.89 mmol) and tert butyldimethylsilylchloride (225 mg, 1.49 mmol) were added and stirring was continued for2.5 h. The reaction mixture was poured into ice-water and extracted with50% AcOEt-hexane. The organic extract was washed with brine, dried overMgSO₄, and evaporated in vacuo. The residue was purified bychromatography on silica gel (30 g) using 5% AcOEt-hexane to afford 14(2.54 g, 97%) in approximately 1α-OH:1β-OH=6.5:1 ratio. The two isomerswere separated by rechromatography on silica gel to give 1α-OTBS 14a and1β-OTBS 14b.

14a (1-αOTBS): ¹H NMR (CDCl₃) δ: −0.02 and 0.02 (each 3H, s, Si—CH₃),0.81 (9H, s, Si-tBu), 1.87 and 2.19 (each 1H, m, 2-H), 2.50 (2H, m,6-H), 4.01 (2H, m, 3, 4-H), 4.27 (1H, m, 1-H), 4.57, 4.63, 4.78 and 4.87(each 1H, d, J=11.8 Hz, CH₂Ph), 7.27˜7.42 (10H, m, arom H).

Mass m/z (%): 440 (M⁺, 3), 383 (2), 349 (3), 333 (5), 308 (7), 277 (6),275 (4), 243 (3), 91 (100).

14b (1-βOTBS): ¹H NMR (CDCl₃) δ: 0.036 and 0.044 (each 3H, s, Si—CH₃),0.86 (9H, s, Si-tBu), 1.90 (1H, dt, J=12.0, 11.0 Hz, 6-H), 2.35 (1H, m,2-H), 2.48 (1H, t, J=12.0 Hz, 6-H), 2.64 (1H, ddd, J=13.1, 4.7, 2.4 Hz,2-H), 3.54 (1H, ddd, J=11.4, 9.4, 4.7 Hz, 3-H), 3.77 (1H, tt, J=11.0,4.5 Hz, 1-H), 4.08 (1H, d, J=9.3 Hz, 4-H), 4.57, 4.65, 4.80 and 4.90(each 1H, d, J=11.6 Hz, CH₂Ph), 7.28-7.41 (10H, m, arom H).

Mass m/z (%): 440 (M⁺, 4), 383 (2), 349 (3), 333 (3), 308 (15), 277(15), 275 (4), 243 (12), 91 (100).

To a stirred solution of 14a (923 mg, 2.09 mmol) in dry THF (10 mL) wasdropwise added L-Selectride (lithium tri-sec-butylborohydride, 1.0 Msolution in THF, 3.14 mmol) at −78° C., and the reaction mixture wasstirred for 1.5 h at the same temperature. The mixture was quenched withice-water and extracted with AcOEt. The organic extract was washed withbrine, and dried over MgSO₄. Removal of the solvent gave the residue,which was chromatographed on silica gel (20 g) using 10% AcOEt-hexane togive 15a (866 mg, 94%) as a sole product. No trace of epimeric alcoholwas detected.

15a (1-αOTBS): ¹H NMR (CDCl₃) δ: 0.04 and 0.06 (each 3H, s, Si—CH₃),0.86 (9H, s, Si-tBu), 1.70 and 1.90 (each 2H, m, 2, 6-H), 3.47 (1H, dd,J=6.9, 3.1 Hz, 4-H), 3.98, 4.05 and 4.10 (each 1H, m, 1, 3, 5-H), 4.63and 4.70 (each 1H, d, J=11.8 Hz, CH₂Ph), 4.67 and 4.69 (each 1H, d,J=10.4 Hz, CH₂Ph), 7.28˜7.40 (10H, m, arom H).

Mass m/z (%): 442 (M⁺, 0.2), 399 (2), 351 (4), 333 (0.2), 293 (2), 277(2), 91 (100).

To a cold (−78° C.) solution of 14b (140 mg, 0.32 mmol) in dry THF (1mL) was added L-Selectride (1.0 M solution in THF, 0.48 mmol) and themixture was stirred for 1.5 h. Work-up similar to that described aboveafforded 15b (107 mg, 76%) as a single isomer together with therecovered starting material 14b (11%).

15b (1-βOTBS): ¹H NMR (CDCl₃) δ: 0.05 (6H, 5, Si—CH₃), 0.87 (9H, s,Si-tBu), 1.37 (2H, m), 2.13 and 2.22 (each 1H, m), 3.40 (1H, dd, J=9.0,3.1 Hz, 4-H), 3.75 (1H, ddd, J=11.7, 9.1, 4.6 Hz, 3 or 5-H), 4.03 (1H,tt, J=11.0, 4.3 Hz, 1-H), 4.12 (1H, dd, J=6.1, 3.1 Hz, 3 or 5-H), 4.66and 4.69 (each 1H, d, J=11.6 Hz, CH₂Ph), 4.68 and 4.78 (each 1H, d,J=11.6 Hz, CH₂Ph), 7.27˜7.37 (10H, m, arom H).

A mixture of 15a (904 mg, 2.04 mmol), sodium hydride (NaH, 60%dispersion in oil, 164 mg, 4.08 mmol) and benzyl bromide (523 mg, 3.06mmol) in dry DMF-dry THF (11 mL, 10:1) was stirred for 4 h at 0° C. Thereaction mixture was diluted with ice-water and extracted with 50%AcOEt-hexane. The organic extract was washed with brine, dried overMgSO₄, and evaporated in vacuo. The residue was purified bychromatography on silica gel (30 g) with 5% AcOEt-hexane to afford 16a(1.02 g, 94%).

16a (1-αOTBS): ¹H NMR (CDCl₃) δ: 0.05 and 0.06 (each 3H, s, Si—CH₃),0.88 (9H, s, Si-tBu), 1.71 (1H, m), 1.92 (2H, m), 2.02 (1H, m),3.69-3.76 (3H, m, 3, 4, 5-H), 3.90 (1H, tt, J=11.0, 4.5 Hz, 1-H), 4.37,4.48, 4.50, 4.55, 4.57 and 4.76 (each 1H, d, J=12.1 Hz, CH₂Ph),7.26˜7.38 (15H, m, arom H).

Mass m/z (%): 532 (M⁺, 0.3), 441 (11), 383 (1), 335 (1), 317 (1), 277(4), 247 (5), 91) (100).

A mixture of 15b (128 mg, 0.29 mmol), sodium hydride (60% dispersion inoil, 23 mg, 0.58 mmol) and benzyl bromide (74 mg, 0.43 mmol) in dryDMF-dry THF (1.65 mL, 10:1) was stirred at 0° C. for 2 h. Work-upsimilar to that described above afforded 16b (141 mg, 92%).

16b (1-βOTBS): ¹H NMR (CDCl₃) δ: 0.04 and 0.05 (each 3H, s, Si—CH₃),0.87 (9H, s, Si-tBu), 1.28 (1H, m), 1.42 (1H, dt, J=12.1, 11.1 Hz), 2.11and 2.25 (each 1H, m), 3.39 (1H, dd, J=9.2, 2.9 Hz, 4-H), 3.90 (2H, m,3, 5-H), 4.03 (1H, tt, J=10.8, 4.5 Hz, 1-H), 4.61-4.77 (6H, m, CH₂Ph),7.27˜7.37 (15H, m, arom H).

A mixture of 16a (1.06 g, 1.99 mmol) and Bu₄NF (1.0 M solution in THF,3.0 mmol) in dry THF (10 mL) was stirred for 30 min at 0° C. followed byat room temperature. After 5 h stirring, additional Bu₄NF (3.0 mmol) wasadded and the reaction mixture was further stirred for 20 h at roomtemperature. The mixture was diluted with ice-water and AcOEt and theorganic phase was separated. The aqueous layer was reextracted withAcOEt and the combined organic extract was washed with brine, dried overMgSO₄, and evaporated to dryness. The residue was purified bychromatography on silica gel (35 g) with 40% AcOEt-hexane to yield 17a(797 mg, 95%).

17a (1-αOH): ¹H NMR (CDCl₃) δ: 1.69-1.80 (2H, m), 2.03˜2.10 (2H, m),3.58(1H, dd, J=6.8, 2.2 Hz, 4-H), 3.94˜4.13 (3H, m, 1, 3, 5-H), 4.61(2H, s, CH₂Ph), 4.63˜4.70 (each 1H, d, J=12.1 Hz, CH₂Ph), 4.72 (2H, s,CH₂Ph), 7.27˜7.34 (15H, m, arom H).

Mass m/z (%): 418 (M⁺, 0.1), 327 (25), 309 (1), 91 (100).

A mixture of 16b (140 mg, 0.26 mmol) and Bu₄NF (1.0 M solution in THF,0.39 mmol) in dry THF (1 mL) was stirred at room temperature. After 2.5h, additional Bu₄NF (0.13 mmol) was added and the mixture was furtherstirred for 2 h. Work-up similar to that described above gave 17b (104mg, 94%).

17b (1-βOH): ¹H NMR (CDCl₃) δ: 1.77 and 1.88 (each 1H, m), 2.07 (2H, m),3.76 and 3.88 (each 1H, m), 4.00 (1H, dt, J=9.4, 3.1 Hz), 4.09 (1H, m),4.55 (2H, s, CH₂Ph), 4.56, 4.62, 4.63 and 4.76 (each 1H, d, J=12.1 Hz,CH₂Ph), 7.27˜7.51 (15H, m, arom H).

Mass m/z (%): 418 (M⁺, 0.2), 341 (1), 327 (15), 309 (1), 91 (100).

A solution of methyl sulfoxide (DMSO, 717 mg, 9.18 mmol) in dry CH₂Cl₂(2 mL) was added slowly to a solution of oxalyl chloride (583 mg, 4.59mmol) in dry CH₂Cl₂ (3 mL) at −78° C. The mixture was stirred for 5 min,and then a solution of 17a (1.60 g, 3.82 mmol) in dry CH₂Cl₂ (7 mL) wasadded dropwise. The reaction mixture was stirred for 15 min and treatedwith triethylamine (1.934 g, 19.1 mmol) for 30 min at −78° C. Thecooling bath was removed, and the mixture was allowed to warm to roomtemperature, and then stirring was continued for 1 h. The reactionmixture was quenched with ice-water and extracted with CH₂Cl₂. Theorganic extract was washed with brine, dried over MgSO₄, and evaporatedin vacuo. The residue was purified by chromatography on silica gel (30g) using 15% AcOEt-hexane to afford 18 (1.50 g, 94%).

18: ¹H NMR (CDCl₃) δ: 2.48 (1H, dm, J=15 Hz), 2.62 (1H, dd, J=13.9, 4.5Hz), 2.79 (1H, dd, J=15.0, 3.9 Hz), 2.87 (1H, dd, J=13.9, 10.5 Hz), 3.99(2H, m, 4, 5-H), 4.06 (1H, ddd, J=10.3, 4.5, 2.3 Hz, 3-H), 4.41, 4.52,4.53, 4.59, 4.70 and 4.86 (each 1H, d, J=12.0 Hz, CH₂Ph), 7.20˜7.36(15H, m, arom H).

Mass m/z (%): 416 (M⁺, 1), 325 (16), 308 (1), 217 (10), 91 (100).

A solution of DMSO (46 mg, 0.59 mmol) in dry CH₂claim₂ (200 μL) wasadded slowly to a solution of oxalyl chloride (38 mg, 0.30 mmol) in dryCH₂Cl₂ (300 μL) at −78° C. The mixture was stirred for 5 min, and then asolution of 17b (104 mg, 0.25 mmol) in dry CH₂Cl₂ (500 mL) was addeddropwise. The reaction mixture was stirred for 15 min and treated withtriethylamine (126 mg, 1.24 mmol) for 30 min at −78° C. The cooling bathwas removed, and the mixture was allowed to warm to room temperature,and then stirring was continued for 1 h. Work-up similar to thatdescribed above afforded 18 (101 mg, 98%).

A mixture of 18 (713 mg, 1.71 mmol) and palladium, 10 wt % on carbon(142 mg) in EtOH (7 mL) was hydrogenolyzed under a atmospheric pressureof H₂ at room temperature. After vigorous stirring for 3 h, AcOEt (7 mL)was added and stirring was continued for additional 2.5 h. The reactionmixture was filtered through a pad of Celite and the filtrate wasevaporated to dryness to yield the crude triol (270 mg).

A mixture of the crude triol (270 mg), triethylamine (693 mg, 6.85mmol), 4-dimethylamionpyridine (105 mg, 0.86 mmol) andtert-butyldimethylsiyl chloride (774 mg, 5.14 mmol) in dry DMF (3.5 mL)was stirred at 0° C. for 4 h. The reaction mixture was poured intoice-water and extracted with AcOEt. The organic extract was washed withbrine, dried over MgSO₄, and evaporated in vacuo. The residue waspurified by chromatography on silica gel (35 g) using 10% AcOEt-hexaneto give 19 (466 mg, 73%).

Intermediate triol: ¹H NMR (CDCl₃) δ: 2.28 (1H, dd, J=14.4, 7.7 Hz),2.46 (1H, dd, J=14.3, 3.6 Hz), 2.53 (1H, dd, J=14.4, 6.3 Hz), 2.66 (1H,dd, J=14.4, 3.6 Hz), 3.75 (1H, d, J=5.2 Hz), 4.03 (1H, m), 4.12 (1H, br.Signal).

Mass m/z (%): 146 (M⁺, 2), 128 (3), 110 (2), 87 (63), 60 (100).

19: ¹H NMR (CDCl₃) δ: 0.07 (6H, s, Si—CH₃), 0.086 and 0.092 (each 3H, s,Si—CH₃), 0.86 and 0.90 (each 1H, s, Si-tBu), 2.25 (1H, dm, J=14.4 Hz),2.46 (1H, ddm, J=13.8, 4.9 Hz), 2.60 (1H, dd, J=13.8, 9.8 Hz), 2.63 (1H,s, OH), 2.77 (1H, dd, J=14.4, 3.5 Hz), 3.80 (1H, m, 4-H), 4.28 (2H, m,3, 5-H).

Mass m/z (%): 374 (no M⁺), 359 (2), 341 (2), 317 (61), 299 (12), 185(95), 143 (100).

¹H NMR and Mass spectra of 19 were in agreement with those reported.Sicinski R R, Perlman K L, DeLuca H F, J. Med. Chem. 1994, 37,3730-3738.

Example 4

(See Scheme IV):

The synthesis of 2-substituted phosphine oxide 23a,b from 19 wasperformed according to the published procedure (Sicinski R R, Perlman KL, DeLuca H F, J. Med. Chem. 1994, 37, 3730-3738).

To a solution of 19 (1.12 g, 2.99 mmol) in dry CH₂Cl₂ (10 mL) was added1-(trimethylsilyl)imidazole (839 mg, 5.98 mmol) at 0° C. After beingstirred for 2 h at the same temperature, water (1.5 mL) was add and themixture was stirred for 30 min. The reaction mixture was extracted withCH₂Cl₂. The organic extract was washed with brine, dried over MgSO₄, andevaporated in vacuo. The residue was purified by chromatography onsilica gel (30 g) with 3% AcOEt hexane to afford 20 (1.32 g, 99%).

20: ¹H NMR (CDCl₃) δ: 0.05 (6H, s, Si—CH₃), 0.06 and 0.07 (each 3H, s,Si—CH₃), 0.16 (9H, s, Si—CH₃), 0.86 and 0.89 (each 1H, s, Si-tBu), 2.17(1H, dm), 2.36 (1H, dd, J=13.7, 4.4 Hz), 2.73 (2H, m), 3.80 (1H, m,4-H), 4.03 (1H, m), 4.24 (1H, ddd, J=10.6, 4.5, 2.3 Hz).

Mass m/z (%): 446 (no M⁺), 431 (7), 389 (100), 315 (4), 299 (99), 257(57), 225 (22).

To a stirred solution of diisopropylamine (601 mg, 5.94 mmol) in dry THF(3 mL) was added butyllithium (BuLi, 1.4 M solution in hexane, 4.24 mL,5.94 mmol) at −78° C. The mixture was stirred for 15 min and methyl(trimethylsilyl)acetate (869 mg, 5.94 mmol) was added. After beingstirred for 10 min at −78° C., a precooled solution of 20 (1.32 g, 2.95mmol) in dry THF (5 mL) was slowly added. The reaction mixture wasstirred for 1.5 h at the same temperature and allowed to warm to 0° C.The mixture was quenched with addition of saturated aqueous ammoniumchloride (NH₄claim) solution, and extracted with AcOEt. The organicextract was washed with brine, dried over MgSO₄, and evaporated todryness. The residue was chromatographed on silica gel (35 g) using 3%AcOEt-hexane to give 21 (1.47 g, 99%) as an unseparable mixture of twoisomers due to newly generated double bond isomerism.

21a (major): ¹H NMR (CDCl₃) δ: 0.04, 0.05, 0.075 and 0.08 (each 3H, s,Si—CH₃), 0.13 (9H, s, Si—CH3), 0.86 and 0.887 (each 9H, Si-tBu), 2.00(1H, dd, J=13.5, 4.7 Hz), 2.60 (1H, dm, J=13.5 Hz), 2.72 and 3.28 (each1H, m), 3.62 (1H, m), 3.68 (3H, s, OCH₃), 3.86 (1H, m), 3.95 (1H, m,3-H), 5.62 (1H, s).

21b (minor): ¹H NMR (CDCl₃) δ: 0.04, 0.05 (each 3H, s, Si—CH₃), 0.06(6H, s, Si—CH₃), 0.13 (9H, s, Si—CH₃), 0.84 and 0.892 (each 9H, Si-tBu),2.12 (1H, dd, J=13.6, 3.8 Hz), 3.66 (3H, s, OCH₃), 3.98 (1H, m), 5.70(1H, s).

21a and 21b: Mass m/z (%): 502 (no M⁺), 487 (4), 445 (90), 413 (9), 385(4), 355 (8), 313 (50), 281 (100).

To a solution of 21a,b (1.47 g, 2.93 mmol) in dry toluene (10 mL) wasadded diisobutylaluminum hydride (1 M solution in toluene, 11.7 mL, 11.7mmol) at −78° C. After being stirred for 1 h at the same temperature,the reaction mixture was quenched with a saturated aqueous sodiumpotassium tartarate solution, and extracted with AcOEt. The AcOEtextract was washed with water, dried over MgSO₄, and evaporated invacuo. The residue was purified by chromatography on silica gel (35 g)using 10% AcOEt-hexane to afford 22a,b (1.36 g, 98%) as a mixture of twoisomers.

22a (major): ¹H NMR (CDCl₃) δ: 0.04, 0.05, 0.058 and 0.07 (each 3H, s,Si—CH₃), 0.13 (9H, s, Si—CH₃), 0.87 and 0.889 (each 9H, Si-tBu), 1.93(1H, dd, J=13.6, 5.4 Hz), 2.24 and 2.38 (each 1H, m), 2.50 (1H, br. D,J=13.0 Hz), 3.56 (1H, m), 3.79 (1H, m), 3.89 (1H, m), 4.12 (2H, m), 5.44(1H, t, J=7.1 Hz).

22b (minor): ¹H NMR (CDCl₃) δ: 0.058 and 0.063 (each 6H, s, Si—CH₃),0.13 (9H, s, SiCH₃), 0.87 and 0.892 (each 9H, Si-tBu), 2.06 (1H, dd,J=13.6, 4.0 Hz), 3.62 (1H, m), 4.05 (1H, m), 5.57 (1H, t, J=7.0 Hz).

22a and 22b: Mass m/z (%): 474 (no M⁺), 441 (2), 399 (28), 349 (5), 325(21), 307 (23), 285 (20), 253 (69), 235 (52), 73 (100).

To a solution of 22a,b (1.35 g, 2.84 mmol) in dry THF (10 mL) was addedn-BuLi (1.4 M solution in hexane, 3.12 mmol) at 0° C., a solution offreshly recrystallized p-toluenesulfonyl chloride (0.595 g, 3.12 mmol)in dry THF (2 mL) was added dropwise, and the mixture was stirred for 5min. n-BuLi (1.4 M solution in hexane, 4.26 mol) was added to a stirred,cold (0° C.) solution of diphenylphosphine (768 mg, 4.2 mmol) in dry THF(3 mL) and the mixture turned orange in color. This orange solution wasslowly added to the above tosylate in THF solution and the mixture wasstirred for 30 min at 0° C. Water (200 μL) was added and the solvent wasevaporated to dryness. The residue was dissolved in CH₂Cl₂ (7 mL) and tothis solution was added 100% hydrogen peroxide (9 mL). The mixture wasstirred for 1 h at 0° C. and CH₂Cl₂ layer was separated. The organicphase was successively washed with cold 2N sodium sulfite, water andbrine, and dried over MgSO₄. After evaporation of the solvent, theresulting residue was purified by chromatography on silica gel (80 g)with 40% AcOEt-hexane to yield 23a,b (1.47 g, 79%) as a mixture of twoisomers.

23a (major): ¹H NMR (CDCl₃) δ: −0.02, 0.00, 0.01 and 0.03 (each 3H, s,Si—CH₃), 0.13 (9H, s, Si—CH₃), 0.82 and 0.87 (each 9H, S I-tBu), 1.86(1H, m), 1.99 (1H, m), 2.08 (1H, m), 2.42 (1H, br. D, J=13.7 Hz), 3.10(2H, m), 3.51 (1H, m), 3.72 (1H, m), 3.82 (1H, m), 5.24 (1H, m).

23b (minor): Most of the signals were overlapped with the major product23a.

23a and 23b: Mass m/z (%): 658 (no M⁺), 643 (4), 601 (100), 526 (19),511 (4), 469 (48), 437 (15), 394 (9).

1. A compound having the formula

where Bn is a benzyl group, and R² is a hydroxy protecting group.
 2. Acompound having the formula

where Bn is a benzyl group, and R² is a hydroxy protecting group.
 3. Thecompound of claim 2 wherein R² is tert-butyldimethylsilyl.
 4. A compoundhaving the formula

where Bn is a benzyl group, and R² is a hydroxy protecting group.
 5. Thecompound of claim 4 wherein R² is tert-butyldimethylsilyl.